Pharmaceutical compositions and methods utilizing substituted bicyclo[2.2.2]-octanes



United States Patent No Drawing. Filed Dec. 28, 1966, Ser. No. 605,19022 Claims. (Cl. 167-65) This application is a continuation-in-part ofcopending application S.N. 569,057, filed Aug. 1, 1966, now abandoned,which in turn is a division of and continuation-in-part of applicationS.N. 449, 896, filed Apr. 21, 1965, now US. Patent No. 3,308,160, whichin turn is a continuation-in-part of application S.N. 290,652, filedJune 26, 1963, now abandoned.

This invention relates to substituted bicyclo[2.2.2]octanes. Moreparticularly, this invention refers to novel 4-phenyl and 4-substitutedphenyl bicyclo[2.2.2]octane l-amines and their use as antidepressants.

According to the present invention I have discovered a novel class ofcompounds which are useful in pharmaceutical applications. Particularly,they are antidepressant agents, as shown by their ability to antagonizetetrabenazine-induced sedation in mice.

The compounds of this invention have the formula where R and R can bethe same or different and each are hydrogen or alkyl of 1 through 4 andpreferably 1 through 2 carbon atoms, or allyl, and where R and R can bejoined together to form -(CH where n is 4, 5 or 6, thus together withthe amine nitrogen forming a pyrrolidino, piperidino orhexamethyleneimino group respectively; and X and Y are hydrogen, methyl,ethyl, chlorine, bromine, fluorine, trifiuoromethyl, nitro, amino,monoalkylamino where the alkyl group has 1 through 4 and preferably 1through 2 carbons, dialkylamino where each alkyl group has 1 through 4and preferably 1 through 2 carbons, hydroxy, cyano, alkoxy of 1 through4 and preferably 1 through 2 carbons, carboxy, and alkoxycarbonyl wherethe alkyl group has 1 through 2 carbons.

Also included within the scope of this invention are where R, R and Xand Y have the same meaning as above and where A is a non-toxic anion.

Representative of the salts of Formula 2 are the hydrochloride, sulfate,phosphate, acetate, succinate, adipate, propionate, tartrate, citrateand bicarbonate. Preferred anions are those derived from hydrochloricacid, acetic acid, phosphoric acid, succinic acid, carbonic acid andcitric acid.

Compounds of the present invention are particularly outstanding where Rand R are hydrogen, X is hydrogen, and where Y is hydrogen or fluorine.Besides hydrogen or fluorine, it is preferred that Y be hydroxy,chlorine, trifiuoromethyl or alkoxy.

The free amines of this invention are generally colorless, low-meltingsolids, soluble in organic solvents. They are moderately basic,comparing with the alkyl amines in this respect. The salts are usuallycolorless, high-melting, crystalline materials, sparingly soluble inwater and insoluble in organic solvents.

The compounds of this invention can be prepared as follows:

4-phenylbicyclo[2.2.2]octane-1-amine is conveniently prepared startingwith 4-hydroxyl-l-phenylbicyclo[2.2.2] octan-Z-one, removing thecarbonyl group from this compound with hydrazine by the Wolif-Kishnersequence, followed by replacement of the hydroxyl group with theacetamido group by the Ritter reaction, followed by alkaline hydrolysis.

Compounds of this invention having the substituents X hydrogen and Yother than hydrogen can be made by nitration of the phenyl ring of an1-acylamido-4- phenyl-bicyclo[2.2.2]octane followed by mild reduction tothe amino compound, diazotization, and reaction of the diazonium saltwith a variety of appropriately selected reagents. Simply heating thediazonium salt in aqueous solution gives the phenol. Reaction with acuprous halide gives the halo-compound, and reaction with cuprouscyanide gives the nitrile. The phenol is alkylated with dialkyl sulfateand base or an alkyl halide and base to give the alkoXy-compound. Thenitrile is hydrolyzed to the carboxylic acid, which isconverted to theester by one of the usual methods such as an alcohol and hydrogenchloride, or the carboxyl group is converted to the trifiuoromethylgroup with sulfur tetrafluoride.

As will be noted, nitration in the above sequence produces primarily thepara substituted derivative although some ortho and meta substitutedproducts will be formed. Separation of the respective ortho, meta andpara-nitro isomers, followed by reduction and diazonium salt formation,gives the desired substituted phenyl l-acylamido bicylcooctane product.

If, instead of diazotization, the amino group is acylated and reducedwith lithium aluminum hydride, it is converted to the alkylamino group.Repetition of this gives the dialkylamino grouping.

After the desired transformation of the phenyl ring has been carriedout, the l-acylamido group is converted to the amino group byhydrolysis, or it can be reduced with lithium aluminum hydride to thel-alkylamino group, and then further acylated and reduced to thel-dialkylamino group.

An alternative method of synthesis of the compounds of this inventionstarts with 4-phenylbicyclo[2.2.2]oet-2- ene-1-carboxylic acid (for thepreparation of 4-phenylbicyclo[2.2.2]octane-l-amine) or a 4-(substitutedphenyl) bicycle[2.2.2]oct-2-ene-l-carboxylic acid (for the preparationof the 4-(substituted phenyl)bicyclo[2.2.2]octanel-amines.) Thepreparation of these compounds which can serve as intermediates forpreparation of compounds of the present invention is disclosed incopending application Ser. No. 377,132, filed June 22, 1964, nowabandoned, and assigned to my assignee.

The unsaturated acid is reduced, conveniently by hydrogen-platinum, toyield the saturated 4-phenyl or 4- (substituted phenyl)bicyclo[2.2.2]octane-l-carboxylic acid, and this is converted to the4-phenyl or 4-(suhstituted phenyl)bicyclo[2.2.2]octane-1-amine by theHolimann, Curtius or Schmidt reactions. The Schmidt reaction, involvingthe use of sodium azide and sulfuric acid, is particularly convenient.

N-alkyl and N,N-dialkyl amines are made by acylation and reduction ofthe N-acyl compound. Although other means such as catalytichydrogenation can be used, lithium aluminum hydride is excellent forthis. Acylatiou can be carried out with many different reagents such asacyl halides, acid anhydrides, carboxylic acid esters, and freecarboxylic acids (especially in the case of the use of formic acid tomake the formyl compounds). An adaptation of this method, where theacylating agent is a dicarboxylic acid anhydride, is used to make thealkyleneirnine compounds. Alternatively, the amino compounds can bealkylated directly with alkyl halides and base or dialkyl sulfates andbase, but this is less preferred than acyiation and reduction.

Another method for making the compounds of this invention involves theammonolysis or aminolysis of the methanesulfonic acid esters of the4-hydroXy-1-phenyl (and substituted phenyl) bicyclo[2.2.2]octanesobtained from the Wolif'Kishner sequence described earlier. Byappropriate choice of the amine reagent, groups R and R can be variedalmost at will. Of course, the use of ammonia as the reagent yields theprimary amine.

Illustrative of the compounds of this invention are the following.Non-toxic salts of these compounds are of course included as mentionedabove:

4-phenylbicyclo[2.2.2]octane-1-amine N-methyl-4-phenylbicyclo [2.2.2]octane-l-amine N,N-dimethyl-4-phenylhicyclo[2.2.2]oetane-1-amineN-ethyl-4-phenylbicyc1o [2.2.2] octane-l-amineN-ethyl-N-methyl-4-phenylbicyclo[2.2.2]octane-1-amineN,N-diethyl-4-phenylbicyclo[2.2.2]octane-1-amineN-propyl-4-phenylbicyc1o[2.2.2]octane-1-amineN-methyl-N-propylt-phenylbicyclo [2.2.2] octane-1- amineN-methyl-N-isopropyl-4-phenylbicyclo [2.2.2] octane-1- amineN-isopropy1-4-phenylbicyclo [2.2.2] octane-l-amineN-ethyl-N-propyl-4-phenylbicyc1o [2.2.2]octane-1-amineN-ethyl-Nisopropyl-4-phenylbicyclo[2.2.2] octane-1- amineN,N-dipropyl-4-phenylbicyclo [2.2.2] octane- I amineN,N-diisopropyl-4-phenylbicyclo [2.2.2] octane-1 -amineN-butyl-N-methyl-4-phenylbicyclo [2.2.2] octane-1- amineN-isobutyl-N-methyl-4-phenylhicyclo[2.2.2]octane-1- amineN-sec-butyi-N-methyl-4-phenylbicyclo [2.2.2] octane-1- amineN-tert-butyl-N-methyL4-phenylbicyclo [2.2.2] octane-1- amineN-isobutyl-4-phenylbicyclo [2.2.2]octane-1-amineN-sec-butyl-4-phenylbicyclo[2.2.2]octane-1-amiueN-tert-butyl-4-phenylbicyclo [2.2.2] octane-l-amine N- (4-pheny1bicyclo[2.2.2] octyl-1-) pyrrolidine N-(4-phenylbicyclo [2.2.2]octyl-1-)piperidine N- (4-phenylbicyclo [2.2.2]octy1-1-)hexarnethyleneimine N- (4-p-chlorophenylhicyclo 2.2.2] octyl-1- pyrrolidine N- (4-p-methoxyphenylbicyclo [2.2.2] octy1-1-) piperidineN- (4-p-trifluoromethylphenylbicyclo [2.2.2] octyl-1-)hexarnethyleneimine N- (4-m-fluorophenylbicyclo [2.2.2]octy1-1-)pyrro1idine N-(4-o-bromophenylbicyclo [2.2.2] octyl-1-)piperidine N-(4-oaminophenylbicyc1o[2.2.2] octyl-1-)hexamethyleneimine4-o-tolylbicyclo [2.2.2 octanel -arnine 4-m-toly1bicyclo [2.2.2]octane-l-amine 4-p-toly-lbicyclo[2.2.2]octane-1-amine4-p-ethylphenylbicyclo [2.2.2] octanel-amine 4- (2,4-dimethylphenyl)bicyclo [2.2.2] octanel-amine 4- (3 ,S-dimethylphenyl) bicyclo [2.2.2]octanel-atnine 4-(2,6-dimethylphenyl)bicyclo[2.2.2]octane-1-amine4-(4-ethy1-2-methylphenyl)bicyclo [2.2.2]octane-1-amine4-(2,4-diethylphenyl bicyclo [2.2.2] octane-l-amine4-p-fluorophenylbicyclo [2.2.2] octane-l-amine 4-p-chlorophenylbicyclo[2.2.2] octane-1 -arnine 4-p-bromophenylbicyclo[2.2.2]octane-1-amine4-o-chlorophenylbicyclo [2.2.2] octanel-amine 4-o-bromophenylbicyclo[2.2.2]octane-1-amine 4-p-trifluoromethylphenylbicyclo 2.2. 2] octane-1-amine 4-0-trifluoromethylphenylbicyclo [2.2.2]octane-1-amine4p-nitrophenylbicyclo [2.2.2] octane-1amine 4-p-aminophenylbicyclo[2.2.2] octane-l-amine 4-m-aminophenyl'bicyclo [2.2.2] octane-1 -amine4-o-aminophenylhicyclo[2.2.2]octane-1-amine 4-(p-methylaminophenyl)bicyclo [2.2.2]octane-1-amine4-(o-butylaminophenyl)bicyclo[2.2.2]octane-1-amine4-(p-dimethylaminophenyl) bicyclo [2.2.2]octane-1- amine4-(m-di-sec-butylaminophenyl) bicyclo [2.2.2] octane-1- amine4-p-hydroxyphenylbicyclo [2.2.2] octanel-amine 4-p-methoxyphenylbicyclo[2.2.2] octane-l-amine 4-p-ethoxypheny1bicyclo [2.2.2]octane-1-amine4-p-isobutoxyphenylbicyclo[2.2.2]octane-1-amine4-p-carboxyphenylbicyclo[2.2.2]octane-1-amine 4-o-carboxyphenylbicyclo[2.2.2] octane-l-amine 4-p-ethoxycarhonylphenylbicyc lo[2.2.2]octane-1-amine 4-p-methoxyearbonylphenylbicyclo[2.2.2] octane-1-amine 4-(2,4-difluorophenyl) bicyclo [2.2.2] octanel-amine 4-(2-chloro-4-fluorophenyl) bicyclo [2.2.2] octane-1- amine 4-(4-fluoro-2-trifiuoromethylphenyl bicyclo [2.2.2] octanel-amine 4-(2,4-dimethoxyphenyl) bicyclo [2.2.2] octane-1 -amine4-(3,4-dimethoxyphenyl) bicyclo [2.2.2]octane-1-amine4-(2,4-dinitrophenyl)bicyclo[2.2.2]octane-1-arnine4-(2,4-dihydroxyphenyl)bicyclo[2.2.2]octane-1-amine 4-(4-hydroXy-2-rnethy1phenyl) bicyclo [2.2.2] octane-1- amine 4- (4-carboXy-2-triflu0romethylphenyl) bicyelo [2.2. 2]

octane-l-arnine 4-(2,3-diaminophenyl) bicyclo[2.2.2]octane-1-amineN-methyi-4-p-chlorophenylbicyclo [2.2.2] octane-LemmeN,N-dimethyl-4-p-chloropheuylbicyclo [2.2.2] octane-1- ammeN-methyl-4-p*trifluoromethylphenylbicyclo [2.2.2] octanel-amineN,N-dimethyl-4-p-trifluoromethylphenylbicyclo[2.2.2]

octane- 1 -amine N-methyl-4-p-methoxyphenylbicyclo [2.2.2] octane-1-amine N,N-dimethyl-4-p-methoxyphenylbicyelo [2.2.2] octanel-amine Nethyl-4-(p-ethylamino)phenylbicyclo [2.2.2] octane-1- amine Particularlypreferred for their effectiveness and combination of desired propertiesare the following compounds and their salts, especially theirhydrochlorides:

4-phenylbicyclo [2.2.2]octane-1-amine N-methy1-4-phenylbicyclo[2.2.2]oetane-1-amine N-ethyl-4-phenylhicyclo [2. 2. 2] octane- 1 -amine4-p-methoxyphenylbicyclo [2.2.2] octane-l-amiue4-p-trifluoromethylphenylhicyclo [2.2.2] octanel-amine4-p-fiuorophenylbicyclo [2.2.2] octane-l-amine4-p-hydr-oxyphenylbicyclo[2.2.2]octane-1-amine 4-p-nitropheny1bicyclo[2.2.2] octane-l-amine4-(2,4-difiuoropheny1)bicyclo[2.2.2]octane-1-amine 4-(2,6-difiuorophenyl) bicyclo [2.2.2] octanel-amine 4-ptolylbicyclo[2.2.2] octane- 1 amine 4- (2,4-dimethylphenyl bicyclo [2.2.2]octanel-amine This invention will be better understood by reference tothe following illustrative examples in which parts and percentages areby weight unless otherwise indicated.

Example 1 A mixture of 42.5 grams (0.197 mole) of 4-hydroxy-1-phenylbicyclo[2.2.2]octan-2-one (I. Colonge and R. Vuillemet, Bull, Soc.Chim. France, 1961, 2235), 100 milliliters of absolute ethanol and 50milliliters of hydrazine hydrate is refluxed 4 hours on a steam bath andallowed to cool to room temperature. The crystals which separate arefiltered, washed with two 50-milliliter portions of absolute ethanol anddried in vacuo at 60 C. The yield of4-hydroxy-l-phenylbicyclo[2.2.2]octan-2- one, hydrazone is 32.70 gramsof light yellow crystals, M.P. 208.4-2ll.0 C.

A 500-milliliter round-bottom flask is fitted with a stirrer, condenserand thermometer and arranged for heating with a mantle. It is chargedwith 23.04 grams (0.100 mole) of4-hydroxy-l-phenylbicyclo[2.2.2]octan-2-one, hydrazone, 2 milliliters ofhydrazine hydrate, 250 milliliters of diethylene glycol and grams ofpotassium hydroxide. The mixture is stirred and heated at 140 C. forthree hours; then, the temperature is raised to reflux and the mixtureis stirred and refluxed for 16 hours. It is cooled to room temperature,poured into 1500 milliliters of water, and the precipitate is filtered,washed with water, and dried in vacuo at 60 C. The yield is 16.1 gramsof a brown solid, 4-phenylbicyclo[2.2.2]octan-1- 01. This is suitablefor the next step, but it can if desired be recrystallized from Water togive a purified product as matted, fine, colorless needles, M.P.122.8123.8 C.

A mixture of 22.7 milliliters of concentrated sulfuric acid, 11.37 gramsof 4-phenylbicyclo[2.2.2]octan-1-ol and 91 milliliters of acetonitrileis refluxed one hour on a steam bath and then poured into 1000milliliters of water. The precipitate is filtered, washed with water anddried in vacuo at 60 C. The yield of 1-acetamido-4-phenylbicyclo[2.2.2]octane is 8.63 grams of a light tan solid. This is suitable forthe next step, but it can if desired be recrystallized from 1:1 absoluteethanol-water to give an oil-white, crystalline solid, M.P. 231.5233.0C.

A mixture of 7.63 grams of 1-acetamido-4-phenylbicyclo[2.2.2]octane, 100milliliters of diethylene glycol and grams of sodium hydroxide isrefluxed 48 hours in a 250-milliliter round bottom flask with stirrer,thermometer and condenser. It is cooled to room temperature, dilutedwith 300 milliliters of water and steam-distilled until the distillateis clear. The distillate is made strongly acidic with concentratedhydrochloric acid. A precipitate of4-phenylbicyclo[2.2.2]octane-l-amine, hydrochloride separates asglistening leaflets. This is filtered and dried in vacuo at 60 C. Theyield is 1.85 grams. Another 1.06 grams can be recovered from thefiltrate. For purification, the crude material is recrystallized fromwater, giving colorless platelets, melting above 300 C.

Analysis.CalCd for C H ClN: N, 5.89. Found: N, 6.02.

Example 2 A 250-milliliter flask with reflux condenser, drying tube andstirrer is charged with 0.10 mole of l-acetamido-4-phenylbicyclo[2.2.2]octane (see Example 1), 100 milliliters ofdiethylene glycol dimethyl ether, and 5.7 grams (0.15 mole) of lithiumaluminum hydride. The mixture is heated for 8 hours at 60 C. and for 2hours at 120 C. After cooling, the reaction mixture is treated withwater to decompose the excess lithium aluminum hydride. The insolublealuminum compounds are dissolved by adding a 20% solution of sodiumpotassium tartrate. The mixture is extracted with ether, the etherextract is dried with anhydrous potassium carbonate, and concentrated invacuo. The residue is suspended in 50 milli- 6 liters of water, taken topH 2 with concentrated hydrochloric acid, and the resulting solution isextracted with ether to remove any traces of unreacted startingmaterial. The raflinate is concentrated in vacuo to yield solidN-ethyl-4-phenylbicyclo[2.2.2]octane-l-amine hydrochloride.

Example 2A A 1000-ml. round-bottom flask is fitted with a stirrer,powder addition funnel, thermometer, condenser with drying tube, and aheating mantle, and is thoroughly dried by flaming while a stream of drynitrogen is passed through the apparatus. It is allowed to cool, andthen 250 ml. of diethylene glycol, dimethyl ether and 5.00 g. (0.13mole) of lithium aluminum hydride are charged, the hydride in smallportions. Then, 39.13 g. (0.16 mole) ofl-acetamido-4-phenylbicyclo[2.2.2]octane is charged from the powderaddition funnel over a period of about /2 hour. The temperature at theend of charging is about 60 C. The mixture is stirred, heated to reflux,and held at reflux (160 C.) for two hours. It is cooled to 15 C. and 15ml. of water is added dropwise, (cautiously), with stirring, followed by25 g. of sodium potassium tartrate in ml. of Water, added all at once.The mixture, which contains some solids, is extracted with two 250-ml.and one 100-ml. portions of ether. The ether extracts are combined,washed with 300 ml. of water, and dried over potassium hydroxidepellets. The ether is vacuum-evaporated to yield 37 g. of crudeN-ethyl-4- phenylbicyclo[2.2.2]octane-l-amine as a brown oil. This istaken up in a boiling solution of 200 ml. of cone. hydrochloric acid in4800 ml. of water, is filtered hot to free the solution of a smallamount of brown scum, and is allowed to cool to room temperature andcrystallize. The crystals are filtered, washed with water and dried. Theyield of N-ethyl-4-phenylbicyclo[2.2.2]octane-1- amine hydrochloride is15.0 g. This is recrystallized from 450 ml. of butyl alcohol, to yield10.5 g. of pure N- ethyl 4 phenylbicyclo[2.2.2]octane-l-aminehydrochloride, which does not melt at temperatures below 300 C.

Analysis. Calcd for C H NCI: C, 72.29; H, 9.10; N, 5.27. Found: C,72.38; H, 9.26; N, 5.36.

Example 3 A solution of 0.10 mole of4-phenylbicyclo[2.2.2]octane-l-amine (prepared by neutralization of anaqueous solution of the hydrochloride followed by ether extraction andthen by evaporation of the ether) in 46.3 grams (1.0 mole) of 98100%formic acid is allowed to stand 18 hours at room temperature. Themixture is concentrated in vacuo to give a residue of1-formamido-4-phenylbicyclo [2.2.2] octane.

1-formamido-4-phenyl-bicyclo[2.2.2]octane is reduced toN-methyl-4-phenylbicyclo[2.2.2]octane-l-amine with lithium aluminumhydride by substituting this compound for1-acetamido-4-phenylbicyclo[2.2.2]octane in the procedure of Example 2,using a 0.10 mole quantity.

Example 3A A mixture of 7.19 g. (0.0358 mole) of 4-phenylbicyclo[2.2.2]octane-1-amine and 25 ml. of butyl formate is heated at refluxC.) for 16 hours in a 100-ml. round bottom flask fitted with athermometer, condenser with drying tube, heated with a mantle. Themixture is allowed to cool to room temperature, and the crystals whichseparate are filtered, washed with 10 ml. of 50% ethanol, and dried. Theyield of 1-formamido-4-phenylbicyclo [2.2.2]octane, M.P. 1725-1735 C.,is 4.45 g. (54%).

Analysis.Calcd for C H NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.92;H, 8.39; N, 6.02.

A 100-ml. round-bottom flask is fitted with a thermometer, condenserwith drying tube, and heating mantle, and arranged for magneticstirring. The apparatus is flamed while dry nitrogen is passed throughit, and is 75 allowed to cool. It is charged with 35 ml. of anhydrousdiethylene glycol, dimethyl ether, 1.03 g. (0.0270 mole) of lithiumaluminum hydride, and 3.10 g. (0.0135 mole) of1-fcrmarnido-4-phenylbicyclo[2.2.2]octane. The reaction mixture isstirred and heated at reflux (160 C.) for 2 hours, then cooled to 15 C.,and the excess lithium aluminum hydride is destroyed by cautiousdropwise addition of water While cooling and stirring. The mixture istransferred to a separatory funnel with 50 m1. of sodium hydroxide andextracted with three 50-m1. portions of ether. The ether extracts arecombined, washed with 30 ml. of water, and dried over solid potassiumhydroxide. The ether is removed by vacuum-evaporation to yield a liquidresidue, which is taken up in a hot solution of 10 ml. of cone.hydrochloric acid in 115 ml. of boiling water. The solution is filteredwhile hot and allowed to cool and crystallize. The crystals are filteredand dried. The yield of pure N-methyl-4phenylbicyclo[2.2.2]octane-1-amine hydrochloride is 2.45 g. It does not melt below300 C.

Analysis.Calcd for C H NCl: C, 71.55; H, 8.81; N, 5.56. Found: C, 71.70;H, 9.36; N, 5.58.

Example 3B To a mixture of 3.56 g. (0.015 mole) of4-phenylbicyclo[2.2.2]octane 1 amine hydrochloride, 1.2 g. (0.03 mole)of sodium hydroxide, and 40 ml. of water is added a solution of 1.82 g.(0.015 mole) of allyl bromide in 2 ml. of carbon tetrachloride. Themixture is heated under reflux overnight with vigorous stirring. Thecooled mixture is extracted with m1. of carbon tetrachloride. The carbontetrachloride extract is dried with anhydrous magnesium sulfate,filtered, and concentrated to give an oily product. The pureN-allyl-4-phenylbicyclo[2.2.2] octane-l-amine obtained from the crudeoil by means of preparative gas chromatography is dissolved in dryether, and the ether solution is treated with dry hydrogen chloride gas.The N allyl-4-phenylbicyclo[2.2.2]octane-1- amine hydrochloride isisolated by filtration and dried; M.P. 281-284".

Analysis.Calcd for C l-I ClN: C, 73.49; H, 8.71; N, 5.04. Found: C,73.20; H, 8.88; N, 5.07.

Example 4 A solution of 0.10 mole of N-methyl-4-phenylbicyclo[2.2.2]octane-1-amine in 46.3 grams (1.0 mole) of 98- 100% formic acidis allowed to stand 18 hours at room temperature, and the mixture isconcentrated in vacuo. The residue consists of Nmethyltormamidol-phenylbicyclo [2.2.2 octane.

N methylformamido-4-phenylbicyclo[2.2.2]octane is reduced toN,N-dimethyl-4-phenylbicyclo[2.2.2] octane-1- amine with lithiumaluminum hydride by substituting this compound for1-acetamido-4-phenylbicyclo[2.2.2]octane in the procedure of Example 2using a 0.10 mole quantity.

Example 4.4

A 100-n1l. round-bottom flask is equipped with a stirrer, thermometerand condenser, and is arranged for heating on a steam bath. It ischarged with 10.06 g. (0.050 mole) of 4-phenylbicyclo[2.2.2]octane-1-amine, 11.8 g. (0.25 mole) of 98% formic acid, and 19.7 g.(0.25 mole) of 37% formalin. The mixture is stirred and heated overnighton the steam bath, and is then cooled, transferred to a 500-ml.Erlenmeyer flask with 100 ml. of water, and made strongly basic with 50%sodium hydroxide, cooling the flask in ice. The cool solution istransferred to a separatory funnel and extracted with one 100-m1. andtwo 50-ml. portions of ether. The ether extracts are combined, washedwith 10 ml. of water, and dried over solid potassium hydroxide. Theether is removed by vacuum-evaporation to yield a residue of colorlesscrystals. These are taken up in a hot solution of 25 ml. of cone.hydrochloric acid in 150 ml. of Water, which is filtered hot and allowedto cool and crystallize. The crystals are filtered and dried to yieldpure N,N-dimethyl-4-phenylbicyclo [2.2.2]octanel-amine hydrochloride,M.P. 2390-2405 C. Analysis shows this material to contain /2 mole ofwater for each mole of amine hydrochloride.

Analysis.Calcd for C H NCL /2H O: C, 69.91; H, 9.17. Found: C, 69.98; H,9.26

Non-aqueous titrationCalcd: 275. Found: 274.

Water (Karl Fisher)-Calcd: 3.28. Found: 3.28.

Example 5 A 1000-ml. round-bottom flask is fitted with a stirrer,thermometer and a pressure-equalized dropping funnel, and is chargedwith 50.25 g. (0.25 mole) of 4-phenylbicyclo[2.2.21octan-1-ol and 300ml. of pyridine. The mixture is stirred until the solids dissolve, andthen 57 g. (0.50 mole) of methanesulfonyl chloride is dropped in over a15-minute period. A small amount of ice-Water bath cooling is used tokeep the temperature at 30 C. or below. The mixture is stirred for 4hours at room temperature, and is then cooled in an ice-Water bath andstirred wln'le 50 ml. of water is added dropwise at such a rate that thetemperature does not exceed 40 C. The mixture is then poured into amixture of 1000 ml. of water plus 1000 g. of ice plus 1 lb. of conc.hydrochloric acid. The crystals which separate are filtered, washed wellwith water, and dried at 60 C./100 mm. The yield ofl-(methanesulfonyloxy) 4 phenylbicyclo[2.2.2]octane, M.P. 132.0l33.0 C.,is 47 g. A small sample which is recrystallized from absolute ethanolhas M.P. 133.0- 134.5 C.

Analysis.Calcd for C I-1 0 8: C, 64.26; H, 7.19; S, 11.44. Found: C,64.58; H, 7.13; S, 11.43.

A mixture of 10.0 g. of 1-(methanesulfonyloxy)-4-phenylbicyclo[2.2.2]octane and 37 g. of butylamine is heated and shakenat 200 C. in a sealed reactor (Hastelloy B) for 6 hours, and is thencooled. Volatile material is removed by vacuum-evaporation, and theresidue is suspended in ml. of 20% sodium hydroxide solution. Thesuspension is extracted with one -ml. and two 25-ml. portions of ether,and the ether extracts are combined, washed with 25 ml. of Water, anddried over solid potassium hydroxide. The ether is removed byvacuum-evaporation to yield an oil, which is taken up in a boilingsolution of 10 ml. of cone. hydrochloric acid in 1000 ml. of water. Theboiling mixture is filtered to remove a small amount of insoluble oil,and is allowed to cool and crystallize. The crystals are filtered,washed with water, and dried at 60 C./ mm. to give 4.55 g. of crudeN-butyl-4-phenylbioyclo[2.2.2]octane-1-amine hydrochloride. After tworecrystallizations from butyl alcohol, the pure amine hydrochloridemelts at 245.5- 246.5 C.

Analysis.-Calcd for C H NCl: C, 73.57; H, 9.60; N, 4.77. Found: C,73.85; H, 9.56; N, 4.82.

Example 6 A solution of 0.10 mole of N-methyl-4-pheny1bicyclo[2.2.2]octane-1-amine in 75 milliliters of dry pyridine is stirred while7.85 grams (0.10 mole) of acetyl chloride is added dropwise at such arate that the temperature does not exceed 60 C. The mixture is thenrefluxed for /2 hour, cooled and poured into 500 milliliters of coldwater. The resulting precipitate is filtered, washed well with water anddried to give 1-N-methy1acetamido-4-phenylbicyc1o[2.2.2]octane.

By using 0.10 mole of 1-N-methylacetamido-4-phenyl--bicyclo[2.2.2]octane for the 1-acetamido-4phenylbicyclo [2.2.2]octaneof Example 2, there is obtained N-ethyl-N- methyl-4-phenylbicyclo[2.2.2] octanel-amine.

Example 6A A 100-ml. round-bottom flask is equipped with a condenser andarranged for magnetic stirring and heating with a mantle. It is chargedwith 9.62 g. (0.0362 mole) of N ethyl 4phenylbicyclo[2.2.2]octane-l-amine hydrochloride, 17.70 g. (0.218 mole)of 37% formalin,

10.20 g. (0.218 mole) of 98% formic acid, and 2.72 g. (0.040 mole) orsodium formate. The mixture is stirred and heated at reflux for 4 hours.Gas is evolved during the heating-up period, and the solids dissolve.The mixture is cooled, 4 ml. of cone. hydrochloric acid is added, andthe mixture is vacuum-evaporated to a pasty mass. This is transferred toa separatory funnel with a solution of 50 ml. of 50% sodium hydroxide in100' ml. of water, and extracted with one 200-ml. portion and one100-ml. portion of ether. Some solids remain. The ether extracts arecombined, washed with 50 ml. of sodium hydroxide, and dried over solidpotassium hydroxide. The ether is removed by vacuum-evaporation to yield6.92 g. of oil-white crystals of crude N-ethyl-N-methyl-4-pheny1-bicyclo[2.2.2]octane-1-amine. This is taken up in a boiling solution of25 ml. of conc. hydrochloric acid in 500 ml. of water, filtered hot, andallowed to cool. The solution is vacuum evaporated, and the residue isground in ether and then filtered and dried to yield 7.25 g. of crude Nethyl N methyl 4 phenylbicyclo[2.2.2]octanel-amine hydrochloride, anoff-white crystalline solid. Recrystallization of this material from 200ml. of benzene yields 3.80 g. of pure Nethyl-N-methyl-4-phenylbicyclo[2.2.2]octane-l-amiue hydrochloride, M.P.217.5- 219.0 C.

Analysis.-Calcd for C H NCl: C, 72.96; H, 9.36; N, 5.01. Found: C,72.79; H, 9.51; N. 4.89.

Non-aqueous titration: Calcd 280. Found 282.

Example 7 A solution of 0.1 mole of 4-phenylbicyclo[2.2.2]octane-l-aminein 50 milliliters of benzene is added slowly to a solution of 0.1 moleof succinic anhydride in 100 ml. of benzene. The mixture is then heatedunder reflux for one hour and the benzene removed by distillation. Anexcess of acetyl chloride, 0.15 mole, is added to the residue and themixture heated under reflux on a steam bath for one hour. The excessacetyl chloride is distilled oil at atmospheric pressure and the aceticacid formed by dehydration of the initially formed succinamic acid isremoved at 100 C. under 15 mm. pressure. The residue is nearly pureN-(4-phenylbicyclo[2.2.2]-octyl-1-) succinirnide. The crude product,after drying in a vacuum desiccator over solid sodium hydroxide pellets,is dissolved in dry tetrahydrofuran and added slowly to a suspension of0.15 mole, an excess, of lithium aluminum hydride in diethyl ether.After complete addition, the reaction mixture is refluxed for 2 hours,the solvent is removed by distillation, and the amine is isolated bysteam distillation. The steam distillate is extracted with ether, thesolution is dried with sodium hydroxide, and dry hydrogen chloride ispassed into the filtered solution until no more is absorbed. Evaporationof the ether yields N (4-phenylbicyclo[2.2.2]octyl-1-)pyrrolidine,hydrochloride.

Example 7A A mixture of 10.0 g. of 1-(methanesulfonyloxy)-4-phenylbicyclo[2.2.2]octane and 40 ml. of redistilled pyrrolidine isheated and shaken at 225 C. in a sealed reactor (Hastelloy B) for 6hours, and is then cooled. The mixture is diluted with 200 ml. of Waterand 75 ml. of cone. hydrochloric acid, transferred to a separatoryfunnel and extracted with two 100-ml. portions of ether. The etherextracts are discarded. The aqueous layer is made strongly basic with50% sodium hydroxide, and is extracted with two 100-ml. portions ofether. The ether extracts are combined, dried with solid potassiumhydroxide, and the ether is removed by vacuum-concentration to yield8.08 g. of a brown oil, crudeN-(4-phenylbicyclo[2.2.2]octyl-1-)pyrrolidine. This is suspended in 25ml. of water and the mixture is adjusted to pH 3 with about 4 ml. ofconc. hydrochloric acid. The clear solution is vacuum-concentrated at 60C. to a semi-crystalline mass, which is dried at 60/100 mm. The driedsolids are extracted with 400 ml. of boiling benzene,

10 which is filtered hot, concentrated to 100 ml. by boiling, andallowed to cool and crystallize. The crystals are filtered and dried,yield 1.67 g. This is recrystallized from 200 ml. of benzene to yield0.81 g. of pure N-(4-phenylbicyclo[2.2.2]octyl l-)pyrrolidinehydrochloride, M.P. 220226 C.

Analysis.-Calcd for C H NCl: C, 74.07; H, 8.98; N, 4.80. Found: C,74.07, C, 74.09; H, 9.27, H, 9.23; N, 4.96.

Example 8 A mixture of 0.10 mole of1-acetamido-4-phenyl-bicyclo[2.2.2]octane (see Example 1) and 100 ml. ofconcentrated sulfuric acid is cooled to 1'0 C. in Dry- Ice-acetone, and9.0 g. (0.10 mole) of concentrated (70%) nitric acid is added dropwisewith stirring. The temperature is kept between 10 and -15 C. during theaddition. Then, the cooling bath is removed and, still stirring, themixture is allowed to warm to room temperature and stir /2 hour. It ispoured into 1000 ml. of ice and water, and the crystals which separateare filtered, Washed with Water, and dried in vacuo at 60 C. Thisproduct is 1 acetamido 4 p nitrophenylbicyclo[2.2.2]octane. It ispurified (separating it from the considerably smaller amounts of them-nitrophenyl and m-nitrophenyl isomers which are formed in thenitration) by recrystallization from absolute ethanol.

A mixture of 0.10 mole of 1-acetamido-4-p-nitrohenylbicyclo[2.2.2]octane and 200 ml. of 20% sulfuric acid is refluxedfor 8 hours, then cooled, diluted with 1000 ml. of water and neutralizedwith 50% sodium hydroxide. The mixture is extracted with three 75-ml.portions of ether, which are combined, washed with Water, dried withanhydrous magnesium sulfate, and concentrated in vacuo to yield 4 pnitrophenylbicyclo[2.2.2]octane-1- amine.

Example 8A A container of a material resistant to hydrogen fluorideattack (as for example, platinum, Hastelloy steel, or polyethylene) iscooled with solid carbon dioxide and acetone and is charged with about50 ml. of anhydrous hydrogen fluoride. The fluid is stirred and 10.50 g.(0.0432 mole) of 1-acetamido-4-phenylbicyclo[2.2.2]octane is added. Then2 ml. (3.00 g., 0.043 mole) of fuming nitric acid is added slowly. Thecooling bath is removed and the solution is allowed to stand for 16 hrs.The hydrogen fluoride is evaporated, the residue is dissolved indichloromethane and is washed with 10% sodium carbonate solution. Thedichloromethane solution is dried with anhydrous magnesium sulfate andevaporated. The residue is recrystallized from alcohol to give 8.73 g.of 1-acetamido-4-(p-nitrophenyl)bicyclo[2.2.2]- octane, M.P. 231233 C.Further recrystallization raises the melting point to 235236.5 C. Thestructure is confirmed by infrared spectroscopy and elemental analysis.

Analysis.-Calcd for C H N O C, 66.64; H, 6.99; N, 9.72. Found: C, 66.32;H, 7.12; N, 9.63.

The l-acetamido 4 (p-nitrophenyl)bicyclo[2.2.2]0ctane is hydrolyzed to4-(p-nitropheny1)bicyclo[2.2.2] octan-l-amine as described in Example 8or as in Example 83 below.

Example 8B A mixture of 2.88 g. (0.010 mole) of 1-acetamido-4-(p-nitrophenyl)bicyclo[2..2.2]octane is refluxed with 50 ml. of 48%hydrobromic acid for 24 hrs. The mixture is cooled, the crystals arefiltered oil to give 4-(p-nitrophenyl)bicyclo[2.2.2]octane-1-aminehydrobromide. The hydrobromide salt is converted to the hydrochloridesalt by adding the crystals to a stirred mixture of saturated potassiumcarbonate solution and ether. The ether extract is dried with anhydrouspotassium carbonate and is then treated with anhydrous hydrogen chlorideto periciptate 4-(p-nitrophenyl)bicyclo[2.2.2]octane 1 aminehydrochloride, M.P. 328330 C. (dec.).

Example 9 A mixture of 0.10 mole of 4-p-nitrophenylbicyclo-[2.2.2]octane-1-amine, 200 ml. of absolute ethanol and 20 ml. of settledW-6 Raney nickel catalyst (J. Am. Chem. Soc., 70, 695 (1948)) ishydrogenated at 50 psi. and 50 C. until hydrogen uptake is complete. Thesolution is filtered and the filtrate is concentrated in vacuo to give4-p-aminophenylbicyclo [2.2.2]octane-1-amine.

Example A mixture of 0.10 mole ofl-acetamido-4-p-nitrophenylbicyclo[2.2.2]octane, 200 ml. of absoluteethanol and ml. of settled W-6 Raney nickel catalyst is hydrogenated at50 p.s.i. and 50 C. until hydrogen uptake is complete. The solution isfiltered and the filtrate is concentrated in vacuo to give1-acetamido-4-p-aminophenylbicyclo[2.2.2]octane. Refluxing this compoundin 10% sodium hydroxide for 8 hours yields4-p-aminophenylbicyclo[2.2.2]octane-l-amine, the product of Example 9.

A solution of 0.10 mole of1-acetamido-4-p-aminophenylbicyclo[2.2.2]octane in 46.3 g. (1.0 mole) of98100% formic acid is allowed to stand 18 hours at room temperature. Themixture is concentrated in vacuo to give a residue of1-acetamido-4-p-formamidophenylbicyclo- [2.2.2]octane.

1-acetamido-4-p-formamidophenylbicyclo [2.2.2] octane is reduced toN-ethyl-4-(pmethylaminophenyl)bicyclo- [2.2.2]octane-1-amine bysubstituting this compound for 1-acetamido-4-phenylbicyclo[2.2.2]octanein the procedure of Example 2, using a 0.10 mole quantity and doublingthe amount of lithium aluminum hydride.

Example 10.4

To a solution of 2.88 g. (0.010 mole) of 1-acetamido-4-(p-nitrophenyl)bicyclo[2.2.2]octane and 2 ml. of hydrazine hydrate in100 ml. of alcohol at 7-0 C. is added W6 Raney nickel until evolution ofgases commences. The mixture is refluxed and after 10 minutes anadditional 2 ml. of hydrazine hydrate is added. The mixture is refluxedfor minutes and is allowed to cool. The catalyst is filtered off, andthe filtrate is evaporated. The residue is recrystallized from tolueneto give 2.26 g. of l-acetamido 4-(p-aminophenyl)bicyclo[2.2.2]octane,M.P. 191.5- 192.5 C.

Analysis.-Calcd for C H N O: C, 74.38; H, 8.58; N, 10.84. Found: C,74.47; H, 8.74; N, 10.91.

A solution of 2.58 g. (0.010 mole) of 1-acetamido-4-(p-aminophenyl)bicyclo[2.2.2]octane, 3 g. (0.10 mole) of sodiumhydroxide, and 20 ml. of methanol is heated in a closed vessel at 200 C.for 8 hrs. The product is dissolved in a mixture of 150 ml. of saturatedpotassium carbonate solution, 50 ml. of water, and 200 ml. ofacetonitrile. The organic layer is separated, dried with anhydrouspotassium carbonate, and evaporated. The residue is dissolved in 50 ml.of 1 N hydrochloride acid, and cone. hyrochloric acid is added toprecipitate 4-(paminophenyl bicyclo [2.2. 2] octanel-aminedihydrochloride, dec. 420 C.

Analysis.-Calcd for C H N -ZHCI: C, 58.13; H, 7.67; N, 9.68. Found: C,57.92; H, 7.68; N, 9.74.

Example 11 A solution of 0.10 mole ofN-ethyl-4-(p-methylarninophenyl)bicyclo[2.2.2]octane-1 amine in 75 ml.of dry pyridine is stirred while 15.70 g. (0.20 mole) of acetyl chlorideis added dropwise at such a rate that the temperature does not exceed 60C. The mixture is then refluxed for one-half hour, cooled and pouredinto 500 ml. of cold water. The resulting precipitate is filtered,washed with. water, and dried to give l-N-ethylacetamidol-(p-N-methylacetarnidophenyl)bicyclo[2.2.2]octane. This is reduced toN,N-diethyl-4-(p-ethylmethylaminophenyl)bicyclo[2.2.2]-octane-1-amine inthe procedure of Example 2, using a 0.10 mole quantity and doubling theamount of lithium aluminum hydride.

Example 12 A mixture of 19.6 g. (0.20 mole) of sulfuric acid, ml. ofwater and 0.10 mole of 1-acetamido-4-paminophenylbicyclo[2.2.2]octane isstirred and cooled to 5 C. with an ice-Water bath. Then, a solution of10.2 g. (0.11 mole) of sodium nitrite in 25 ml. of water is addedslowly, with stirring, keeping the temperature at 5 C. The mixture isallowed to stir one-half hour at 5, and is then heated to 50 C. on thesteam bath, and held at 50 C. for one-half hour. It is cooled andextracted with three 50-ml. portions of ether, and the ether extractsare combined, washed with 25 ml. of water, dried with anhydrousmagnesium sulfate, and concentrated in vacuo to give a residue of1-acetamido-4-p-hydroxyphenylbicyclo [2.2.2] octane.

A mixture of 0.10 mole ofl-acetamidol-p-hydroxyphenylbicyclo[2.2.2.]octane, 100 ml. of'diethylene glycol, and 25 grams of sodium hydroxide is refluxed for 48hours, then cooled and diluted with 300 ml. of water. The mixture isadjusted to pH 8.5 with cone. hydrochloric acid, and then extracted withthree 50-ml. portions of ether. The ether extracts are combined, washedwith 25 ml. of water, dried with anhydrous magnesium sulfate, andconcentrated in vacuo to give a residue of 4-phydroxyphenylbicyclo2.2.2] octane-1 -amine.

Example 12A A mixture of 5.20 g. (0.020 mole) of 1-acetamido-4-(p-aminophenyl)bicyclo[2.2.2]octane and 100 m1. of 1 N H SO is stirredand cooled to 5 C. with an icewater bath. Then a solution of 1.40 g.(0.020 mole) of sodium nitrite in 40 ml. of water is added slowly withstirring so that the temperature does not exceed 5 C. Then 200 ml. ofwater is added and the mixture is refluxed for 30 min. The precipitateis filtered off and is Washed with water. The solid is heated with 200ml. of 10% sodium hydroxide solution in an autoclave at 220 C. for 4hrs. The product is cooled to room temperature and the precipitate isfiltered off and washed with water. The precipitate is added to 1 Nhydrochloric acid, heated to effect solution, and allowed to cool. Thecrystals of 4- p-hydroxyphenyl) bicyclo [2.2.2] octanl-aminehydrochloride are filtered oif, washed with water, and dried. Theproduct decomposes on heating.

Analysis.Calcd for C H NO-HCI: C, 66.26; H, 7.95; N, 5.52. Found: C,66.50; H, 8.03; N, 5.57.

Example 13 A mixture of 0.10 mole of1-acetamido-4-p-hydroxyphenyl-bicyclo[2.2.2]octane, 100 ml. of water,and 5.0 g. of sodium hydroxide is stirred and cooled at 5 C. while 12.6g. (0.10 mole) of dirnethyl sulfate is added dropwise. It is stirred 15minutes at 5 C., then warmed to 75 for 1 hour on the steam bath. Themixture is cooled, extracted with three 50-m1. portions of ether, andthe ether extracts are combined, washed with 25 ml. of water, dried withanhydrous magnesium sulfate, and concentrated in vacuo to give a residueof 1-acetamido-4-pmethoxyphenylbicyclo [2.2.2] octane.

A mixture of 0.10 mole of1-acetamido-4-p-methoxyphenylbicyclo[2.2.2]octane, 100 ml. of diethyleneglycol and 25 g. of sodium hydroxide is refluxed for 48 hours, thencooled and diluted with 300 ml. of water. It is extracted with three50-ml. portions of ether, and the ether extracts are combined, washedwith 25 ml. of water, and

' dried with anhydrous magnesium sulfate. Concentration A mixture of19.6 g. (0.20 mole) of sulfuric acid, 100

ml. of water and 0.10 mole of1-acetamido-4-p-aminophenylbicyclo[2.2.2]octane is stirred and cooled to5 C.

cuprous chloride (0.15 mole), dissolved in 50 ml. of

concentrated hydrochloric acid, stirred well, and the mixture is allowedto warm to room temperature. After standing 15 minutes at roomtemperature, the mixture is heated to 60 C. for one-half hour, thencooled to room tempera-ture, and extracted with three 50ml. portions ofether. The ether extracts are combined, washed with 25 ml. of water,dried with anhydrous magnesium sulfate, and concentrated in vacuo togive a residue of l-acetamido-4-p-chlorophenylbicyclo[2.2.2] octane.

A mixture of 0.10 mole of1-acetamido-4-p-chlorophenylbicyclo[2.2.2]octane, 100 ml. of diethyleneglycol and 25 g. of sodium hydroxide is refluxed for 48 hours, thencooled and diluted with 300 m1. of water. It is extracted with three50ml. portions of ether, and the ether extracts are combined, washedwith 25 ml. of water, dried with anhydrous magnesium sulfate, andconcentrated in vacuo to give a residue of4-p-chlorophenylbicyclo[2.2.2] octane-l-amine.

Example 14A A mixture of 12.9 g. (0.050 mole) of 1-acetamido-4-(p-aminophenylbicyclo[2.2.2]octane and 250 ml. of conc. hydrochloricacid is cooled to C., and a solution of 3.5 g. of sodium nitrite in 20ml. of water is dropped in. The mixture is stirred for 20 min. Then asolution of 5.0 g. of cuprous chloride in 250 ml. of conc. hydrochloricacid is dropped into the solution rapidly. The mixture is allowed towarm to room temperature and then is heated at 55 C. for 16 hours oruntil no further evolution of nitrogen is observed. The mixture isextracted with chloroform, and the extract is washed with water, driedwith water, dried with anhydrous magnesium sulfate, and evaporated. Theresidue is recrystallized from acetonitrile to give1-acetamido-4-(p-chlorophenyl)bicyclo[2.2.2]octane, M.P. 230-233 C.

l-acetamido 4 (p-chlorophenyl)bicyclo[2.2.2] octane is hydrolyzed andconverted to the hydrochloride salt by the method described in Example8B to give 4-(pchlorophenyllbicyclo[2.2.2]octan-1-amine hydrochloride,M.P. 324325 C. (dec.).

Example 1 5 Substitution of 0.10 mole of freshly prepared cuprousbromide in a mixture of 45 g. of conc. sulfuric acid and 500 ml. ofwater for the cuprous chloride in hydrochloric acid solution of Example14 gives 1-acetamido-4- -bromophenylbicyclo[2.2.2]octane, which ishydrolyzed with diethylene glycol and sodium hydroxide in the manner ofthat example to wield 4-p-bromophenylbicyclo[2.2.2]octane-l-amine.

Example 15A 4-(p-bromophenyl)bicyclo[2.2.2]octane 1 amine can beconveniently prepared by direct bromination ofl-acetamido-4-phenylbicyclo[2.2.2]octane. To a solution of 12.2 g.(0.050 mole) of 1-acetamido-4-phenylbicyclo- [2.2.2]octane in 50 ml. ofliquid anhydrous hydrogen fluoride is added 8.0 g. (0.050) mole ofbromine. A small amount of iron powder is added and the mixture isstirred overnight. The hydrogen fluoride is evaporated and the residueis dissolved in chloroform. The chloroform solution is washed with 1 Nhydrochloric acid, dried With anhydrous magnesium sulfate, andevaporated. The residue is recrystallized from alcohol to give 8.73 g.of 1acetamido 4 (p-bromophenyl)bicyclo[2.2.2]octane, M.P. 242-244" C.

Analysis.Calcd for C H BrNO: C, 59.63; H, 6.26; N, 4.35. Found: C,59.57; H, 6.39; N, 4.36.

1 acetamido-4-(p-bromophenyl)bicyclo[2.2.2]-octane is hydrolyzed with48% hydrobromic acid and converted to the hydrochloride salt asdescribed in Example 8B. The

14 product is 4 (p bromophenyl)bicyclo[2.2.2]octane-1- aminehydrochloride, M.P. 325 C. (dec.).

Analysis.-Calcd for C H BrN-HCl: C, 53.10; H, 6.05; N, 4.41. Found: c.53.08; H, 6.16; N, 4.46.

Example 16 A 0.10 mole quantity of1-acetamido-4-p-aminophenylbicyclo[2.2.2]octane is diazotized as inExample 14, and the cold diazonium salt solution is added slowly to a 60C. solution of 0.20 mole of freshly prepared cuprous cyanide solution ina mixture of 20 g. of sodium cyanide and 75 ml. of water in a flaskarranged for steam distillation. The temperature is maintained at 60 C.for one-half hour, then it is raised to reflux for 1 hour, and finallythe mixture is steam-distilled. The steam distillate is cooled,extracted with three 50ml. portions of ether, and the ether extracts arecombined, washed with 25 ml. of Water, dried with anhydrous magnesiumsulfate, and concentrated in vacuo to give a residue of1-acetamido-4-pcyanophenylbicyclo [2.2.2 octane.

A mixture of 0.10 mole ofl-acetamido-4-p-cyanophenylbicyclo[2.2.2]octane, ml. of diethyleneglycol and 25 g. of sodium hydroxide is refluxed for 48 hours, thencooled and diluted with 300 ml. of water, and adjusted to pH 8.5 withcone. hydrochloric acid. The mixture is extracted with three 50ml.portions of ether and the ether extracts are combined, washed with 25ml. of water, dried with anhydrous magnesium sulfate, and concentratedin vacuo to give a residue of 4-p-carboxyphenylbicyclo-[2.2.2]octane-l-amine.

Example 16A A suspension of 9.68 g. (0.0375 mole) of l-acetamido-(4-aminophenyl)bicyclo[2.2.2]octane in 50 ml. of 6 N HCl is cooled to 5C. and diazotized with 2.58 g. (0.0374 mole) of sodium nitrite. Then thesolution is made alkaline with potassium carbonate solution. The mixtureis then poured with stirring into 150 ml. of cold cuprous cyanide(prepared as described in Organic Syntheses, Collective Volume I, p.514). The mixture is allowed to warm to room temperature and stirring iscontinued for 24 hrs. The solid material is filtered off, washed withwater, and dried. The product is recrystallized from xylene to give 4.66g. of 1 acetamido-4-(p-cyanophenyl)bicyclo[2.2.2]-oetane, M.P. 267-269C.

Analysis.-Calcd. for C H N O: C, 76.08; H, 7.51; N, 10.44. Found: C,76.24; H, 7.85; N, 11.03.

Example 17 Hydrogen chloride gas is passed into a solution of 0.10 moleof 4-p-carboxyphenylbicyclo[2.2.2]octane in 100 ml. of absolute ethanol,with cooling, until the solution is saturated at room temperature. Afterallowing the mixture to stand 48 hours at room temperature, the mixtureis concentrated in vacuo to yield a residue of 4-p-ethoxy carboxylphenylbicyclo [2.2.2] octanel-amine, hydrochloride.

Example 17A 1 acetamido-4-(p-cyanophenyl)bicyclo[2.2.2]octane ishydrolyzed by 48% hydrobromic acid and converted to the hydrochloridesalt by the method described in SE. The product is 4-(p-carboxyphenyl)bicyclo[2.2.2]octane-1- amine hydrochloride, dec. 350C. The structure of the product is confirmed by its infrared spectrum.

Analysis.-Calcd for C H NO -HCl: C, 63.93; H, 7.15; N, 4.97. Found: C,63.46; H, 7.09; N, 5.27.

Example 18 A -ml. Hastelloy bomb is charged with 0.10 mole of4-p-carboxyphenylbicyclo[2.2.2]octane-1-amine, 45 ml. of nitromethane,and 43 g.- (0.40 mole) of sulfur tetrafluoride. It is closed and heatedat C. for 8 hours. After cooling and venting, the solvent and excesssulfur tetrafluoride are removed by concentration in vacuo and theresidue is treated with 400 ml. of ice-cold 20% sodium 15 hydroxide.This is extracted with three 50ml. portions of ether, and the etherextracts are combined, washed with 25 ml. of water, dried with anhydrousmagnesium sulfate, and concentrated in vacuo to give a residue of4-p-tri fluoromethylphenylbicyclo[2.2.2]octane-1-amine.

Example 18.4

A suspension of 10.3 g. (0.040 mole) of 1-acetamido-4-(p-aminophenyl)bicyclo[2.2.21octane in 50 ml. of 6 N hydrochloric acidis cooled to C. and diazotized with 2.76 g. (0.040 mole) of sodiumnitrite. Then ml. of 65% hexafluorophosphoric acid solution is added,and the precipitate is filtered off, washed with water, and dried. Thedry precipitate, suspended in 200 ml. of s-tetrachloroethane, isrefluxed for 2 hrs. and then allowed to cool. The solvent is evaporatedOE and the residue is chromatographed on silicic acid with chloroform.There is obtained 6.14 g. of l-acetamidoi-(p-fluorophenyl)-bicyclo[2.2.2]octane, M.P. 189-l91 C.

Analysis.Calcd for C H NOF: C, 73.53; H, 7.71; N, 5.37. Found: C, 73.13;H, 7.76; N, 5.39.

A mixture of 2.61 g. of 1-acetamido-4-(4-tluorophenyl)bicyclo[2.2.2]octane, 25 ml. of diethylene glycol, 1 ml. of water, and 2g. of sodium hydroxide is refluxed for 16 hrs. The product is pouredinto ice-water and extracted with ether. Evaporation of the ether givesa residue that is soluble in hot 3 N hydrochloric acid. On cooling, thesolution gives colorless crystals of 4-(p-fluorophenyl)bicyclo[2.2.2]octan-l-amine hydrochloride, dec. 335 C. The structure isconfirmed by infrared spectroscopy.

Analysis.Calcd for C H FN-HCl: C, 65.74; H, 7.49; N, 5.48. Found: C,65.50; H, 7.64; N, 5.61.

Example 181? To a solution of 24.3 g. of 1-acetamido-4-phenylbicyclo[2.2.2]octane in 100 ml. of anhydrous, liquid hydrogen fluoride is added15.7 g. of acetyl chloride. Boron trifluoride is passed into thesolution and the mixture is stirred for 16 hrs. The boron trifluorideand hydrogen fluoride are evaporated. The residue is dissolved inchloroform, and the solution is washed with potassium carbonate solutionand evaporated. The residue is recrystallized from xylene to give 19 g.of 1-acetamido-4-(p-acetylphenyl)- bicyclo[2.2.2]octane, M.P. 209212 C.

The structure is confirmed by infrared spectroscopy.

A mixture of 2.85 g. of l-acetamido-4-(p-acetylphenyl)-bicyclo[2.2.2]octane and 1 g. of 10% palladium on carbon in 200 ml. ofalcohol is hydrogenated at 3 atrn. for 16 hrs. The catalyst is filteredoff and the filtrate is evaporated. The residue is recrystallized fromheptane to give 2.20 g. of 1-acetamido-4-(p-ethylphenyl)bicyclo[2.2.2]octane, M.P. 156-157 C. The structure is confirmed by infraredspectroscopy.

1 acetamido 4- (p-ethylphenyl)bicyclo[2.2.2] octane is hydrolyzed by themethod described in Example 8B to give4-(p-ethyiphenyDbicyclo[2.2.2]octane-l-amine hydrochloride, M.P. 355359C. (dec.).

Analysis.--Calc-d for C O N-Hcl' fitl-l o: C, 71.09; H, 9.13; N, 5.18;Cl, 13.11. Found: C, 70.85; H, 9.02; N, 5.22; Cl, 12.90.

Example 18C A solution of 40 g. of ethyl 4-phenylbicyclo [2.2.2]oct-Z-ene-l-carboxylate (prepared according to the method described inapplication S.N. 377,132) in 100 ml. of ethanol is hydrogenated for 16hrs. at atmospheric pressure. A solution of 0.2 M chloroplatinic acidinitially is added to the solution until uptake of hydrogen commences.The catalyst is filtered off and the solvent is evaporated. The residueis recrystallized from methanol to give 22.2 g. of ethyl4-phenylbicyclo[2.2.21octane-lcarboxylate, M.P. 6869 C.

A mixture of 11 g. of ethyl 4-phenylbicyclo[2.2.2] octane-l-carboxylateand 1000 ml. of 2 N sodium hydroxide solution is refluxed for 16 hrs.with stirring. The mixture is allowed to cool slightly and is acidifiedwith iii conc. HCl so that the temperature is held at -100 C. Coolingthe acidified solution gives 9.0 g. of 4-phenylbicyclo[2.2.2]octan- 1-carboxylic acid, which can be purified by recrystallization from aceticacid to give crystals, M.P. 277-279 C. A sample purified for analysismelts at 282284 C.

Analysis.Calcd for C I-1 0 C, 78.23; H, 7.88; mol. wt., 230. Found: C,77.76; H, 7.71; mol. wt., 226.

4-phenylbicyclo[2.2.21octan-1-amine can be prepared conveniently from4-phenylbicyclo[2.2.2]octane1-carboxylic acid by the wel1-known Schmidtreaction. To a mixture of 0.024 mole of the acid, 41 ml. of cone.sulfuric acid, and 80 ml. of chloroform is added with stirring at 50-55C., 0.042 mole of sodium azide in small portions. After all the azide isadded, the mixture is heated for another 30 min. at 50 C., diluted withice, and made alkaline. The reaction mixture is steam-distilled and thedistillate is made strongly acid with concentrated hydrochloric acid. Aprecipitate of 4-phenylbicyclo[2.2.2] octanl-amine hydrochlorideseparates. The product is identical with that obtained as described inExample 1.

Example 18D Substitution of ethyl 4-tolylbicyclo[2.2.2]oct-2-ene 1-carboxylate (prepared according to the method described in applicationS.N. 377,132) for ethyl 4-phenylbicyclo [2.2.2]oct-Z-ene-l-carboxylatein the previous procedure gives 4-tolylbicyclo [2.2.2] octane-1-aminehydrochloride.

Example 18E To a mixture of 7.7 g. (0.10 mole) of fuming nitric acid andml. of concentrated sulfuric acid cooled to 0 C. in an ice bath is addedin portions 0.050 mole of 4-phenylbicyclo[2.2.21octane-l-carboxylicacid. The mixture is stirred for one hour and then is poured into oneliter of ice-water. The precipitate is filtered off, washed with water,and dried. The precipitate is recrystallized from toluene to give4-(2,4-dinitrophenyl)bicyclo[2.2.2] octan-1-carboxylic acid as paleyellow crystals, M.P. 242.5-245 C.

Analysis.-Calcd for C H N O C, 56.25; H, 5.04; N, 8.75. Found: C, 56.61;H, 5.09; N, 8.37.

To a mixture of 0.024 mole of 4-(2,4-dinitrophenyl)-bicyclo[2.2.2]octane-l-carboxylic acid, 41 ml. of cone. sulfuric acid,and 80 ml. of chloroform is added with stirring at 50-55 C., 0.042 moleof sodium azide in small portions. After all of the azide is added, themixture is heated for another 30 mins. at 50 C., diluted with ice, andmade alkaline. The organic material is extracted with chloroform, andthe extract is dried with anhydrous potassium carbonate and evaporated.The residue is extracted with hot 1 N HCl and the extract is allowed tocool. The precipitate is filtered off, washed with water, and dried togive 4-(2,4-dinitrophenyl)bicyclo[2.2.2]octan-1-amine hydrochloride.

Example 18F 1-acetamido-4(p-fluorophenyl)bicyclo[2.2.2] octane isnitrated as described in the previous example. The product is a mixtureof isomers, which is separated by chromatography to givel-acetarnido-4(4-fluoro-2-nitrophenyl)-bicyclo[2.2.2]octane and1-acetamido-4-(4-fluoro-3- nitrophenyl)bicyclo[2.2.2]octane. Hydrolysisof these compounds with 48% hydrobromic acid and conversion to thehydrochloride salts by the procedure described in Example 8B givesrespectively 4-(4-fluoro-2- nitrophenyl)bicyclo[2.2.2]octan-1 aminehydrochloride and 4-(4 fluoro-S nitrophenyl)bicyclo [2.2.2] octan 1-amine hydrochloride.

Example 18G Reduction of 1 acetarnido-4-(2-nitro-4-fluorophenyl) bicyclo[2.2.2] octane and 1-acetamido-4- (3-nitro-4-fiuorophenyl)bicyclo[2.2.2] octane by the procedure described in Example 10A givesrespectively 1-acetamido-4-(2- luqmphenyllbicycle[2.2.21octane andl-acet- 17 amido-4-(3-amino-4 fiuorophenyl)bicyclo[2.2.2]octane.Hydrolysis by the procedure described in Example 8B gives respectively4-(2-amino-4-fluorophenyl)bicyclo [2.2.2]octan-1-amine dihydrochlorideand 4-(3-amino-4- fiuorop'henyl)bicyclo[2.2.2]octan-l aminedihydrochloride.

Example 18H Diazotozation, pyrolysis of the diazoniumhexafluorophosphate salts, and hydrolysis by the procedure of Example18A of 1-acetamido-4-(2-amino-4 fluorophenyl)- bicyclo[2.2.2] octane and4-(3-arnino-4-fluorophenyl) bicyclo[2.2.2]octane gives respectively4-(2,4-difluorophenyl)bicyclo[2.2.2] octan-l-amine hydrochloride and4-(3,4- diiiuorophenyl)bicyclo[2.2.2]octan 1 amine hydrochloride.

Example 181 Bromination of l-acetamidoi-tolylbicyclo [2.2.2] octane bythe procedure described in Example A gives a mixture of 1-acetamido-4-(2-bromotolyl)bicyclo[2.2.2] octane and 1-acetarnido-4-( 3bromotolyl)bicyclo [2.2.2]octane, which can be separated bychromatography. Hydrolysis of each isomer by the procedure described inExample 83 gives respectively 4-(2-bromotolyl)bicyclo [2.2.2]octan-lamine hydrochloride and 4-(3-bromotolyl)bicyclo[2.2.2]octan-l-amine hydrochloride.

Example 18] A mixture of 0.1 mole of1-acetamido-4-(p-hydroxyphenyl)bicyclo[2.2.2]octane, 20 ml. of benzene,15 ml. of H 0, and 15 n11. of conc. nitric acid is stirred at roomtemperature for one hour. The mixture is diluted and extracted withbenzene. The benzene extract is dried with anhydrous magnesium sulfateand evaporated to give 1- acetamido-4-(4-hydroXy-3nitrophenyl)bicyclo[2.2.2]octane. Hydrolysis by the procedure in Example8A gives 4- (4-hydroxy-3 nitrophenyl) bicyclo[2.2.2] octan-l-aminehydrochloride.

Example 18K A mixture of 0.05 mole of 1-acetamido-4-hydroxy-3-nitrophenyl)bicyclo[2.2.2]octane, 0.05 mole of methyl sulfate and 0.10mole of potassium hydroxide dissolved in ml. of Water is heatedgradually to 90 until the color of the solution changes and the productseparates. The solution is cooled, diluted, and extracted with ether.The ether extract is washed with water, dried with anhydrous 18 Example18M A mixture of 0.10 mole of 4-phenylbicyclo[2.2.2]octane-l-amine and9.87 g. (0.10 mole) of 38% hydrochloric acid in 100 ml. of Water isconcentrated in vacuo at C. The resulting salt,4-phenylbicyclo[2.2.2]octanel-amine hydrochloride, is dried in vacuo at60 C.

Example 20 A solution of 0.20 mole of4-phenylbicyclo[2.2.2]octane-l-amine, hydrochloride in 200 ml. of hotwater is added to a solution of 0.10 mole of pamoic acid, disodium salt[4,4'-methylenebis-(3-hydroxy-2-naphthoic acid), disodium salt] in 500ml. of Water. The resulting precipitate is filtered, Washed Well withWater, and dried in vacuo at 60 C. to give 4-phenylbicyclo[2.2.2]octane-1- amine, pamoate.

Example 21 Carbon dioxide is passed into a solution of 0.10 mole of4-phenylbicyclo[2.2.2]octane-l-amine in 100 ml. of ether untilprecipitation is complete. The precipitate is filtered and dried invacuo at 60 C., to give 4-phenylbicyclo[2.2.2]octane-1-amine,bicarbonate.

Example 22 Hydrogen chloride (0.10 mole) is passed into a solution of0.10 mole of 4-phenylbicyclo[2.2.2]octane-lamine in 100 ml. of ether.The precipitate is filtered and dried in vacuo at 60 C. to give4-phenylbicyclo[2.2.2]- octane-l-amine, hydrochloride.

Examples 23-31 Example 19 is repeated substituting the followingindicated reactants for those of that example, to obtain the indicatedproduct:

Example No. Product of Example Acid Product 2 (free base) (0.10 mole)85% phosphoric acid (0.10 mole)...Nethyl-4-phenylbicyclo[2.2.2]0ctane-1-amine, phosphate. 3 (0.10 mole)Sulfuric acid (0.050 mole) N-methyl-tphenylbicyclo[2.2.2]octane-1-amine,sulfate. 4 (0. Tartaric acid (0.10 mole)N,N-dimethyl-4-plienylbicyclo[2.2.2]octane1-arnine, bitartratc.

5 (0. Tartaric acid (0.050 mole) N-butyl-i-pheny1bicyclo[2.2.2]0ctane-1-amine, tartrate. 6 (0. Maleic acid(0 050 m0le). N-ethyl-N-methyl-4-plienylbicyclo[2.2.2]octane-1-amine,maleate. 7 (0. Acetic acid (0.10 mole). N-(4-pheny1bicyc1o[2.2.2]octyl-1-)pyrrolidine, acetate. 8 (0. Succinicacid (0.050 mole) 4-p-nitrophenylbicyclo[2.2.2]octanel-amine, succinate.9 Mandelic acid (0.10 mole) 4-p-amin0phcnylbicyclo[octane-1-amine,mandelate]. 13 Lactic acid4-p-methoxyphenylbicyclo[2.2.2]0ctane-1-amine, lactate.

magnesium sulfate and evaporated to give 1-acetamido-4-(4-methoxy-3-nitrophenyl) bicyclo 2.2.2] octane. Hydrolysis of theproduct according to the procedure described in Example 8B gives4-(4-methoxy-3-nitrophenyl)bicyclo [2.2.2]octan-l-amine hydrochloride.

Example 18L Reduction ofl-acetamido-4-(4-methoxy-3-nitrophenyl)bicyclo[2.2.2] octane withhydrazine hydrate and Raney nickel as described in procedure 10A gives1-acetamido-4- (3-amino 4 methoxyphenyl)bicyclo[2.2.2] octane.Hydrolysis of the reduction product according to the procedure inExample 8B gives 4-(3-amino-4-methoxyphenyl) bicyclo[2.2.2]octan-1-aminedihydrochloride.

The preceding examples can be repeated substituting equivalent amountsof appropriate starting materials to obtain other compounds of thisinvention including those listed hereinbefore.

The compounds of this invention can be administered for antidepressanteffect according to this invention by any suitable means. For example,administration can be parenterally, that is subcutaneously,intravenously, intramusc'ularly, or intraperitoneally. Alternatively orconcurrently, administration can be by the oral route.

The dosage of compounds for this invention administered to thewarm-blooded animal will depend on the age, health and Weight of thesaid warm-blooded animal recipient, the frequency of administration andthe intensity of the anti-depressant response desired. Generally, adaily dosage of active ingredient compound will be from about 0.05 to 50mg. per kg. of body weight, although lower, such as 0.01 mg./kg., orhigher amounts can be used. Ordinarily, from 0.1 to 20 and preferably0.1 to mg/kg. per day, in one or more applications per day, is effectiveto obtain the desired result.

The hydrochloride salt of 4-phenylbicyclo[2.2.2]oc tane-l-amine, acompound for this invention, strongly indicates anti-depressant activityas demonstrated in mouse tests where a single oral dose of the abovenamed compound, in a concentration of 0.5 mg. per kg. of body weight,administered orally demonstrated successful protection againsttetrabenazine induced sedation.

Besides the active ingredient of this invention the composition willcontain a solid or liquid non-toxic pharmaceutical carrier for theactive ingredient.

In one embodiment of a pharmaceutical composition of this invention, thesolid carrier is a capsule which can be of the ordinary gelatin type. Inthe capsule will be from about l50% by weight of a compound of Formula 1or 2 and 99-50% of a carrier. In another embodiment, the activeingredient is tableted with or without adjuvants. In yet anotherembodiment, the active ingredient is put into powder packets andemployed. These capsules, tablets and powders will generally constitutefrom about 1% to about 95% and preferably from 1% to 50% by weight ofactive ingredient. These dosage forms preferably contain from about 1 toabout 500 mg. of active ingredient, with from about 1 to about 100 mostpreferred.

The pharmaceutical carrier can, as previously indicated, be a sterileliquid such as Water and oils, including those of petroleum, animal,vegetable or synthetic origin, for example peanut oil, soybean oil,mineral oil, sesame oil, and the like. In general, water, saline,aqueous dextrose (glucose) and related sugar solutions and glycols suchas propylene glycol or polyethylene glycols are preferred liquidcarriers, particularly for injectable solutions. Sterile injectablesolutions such as saline will ordinarily contain from about 0.05% to andpreferably about 0.1 to 1% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspensionor syrup, in which the active ingredient ordinarily will constitute fromabout 0.02 to 10%, and preferably about 0.1 to 1% by weight. Thepharmaceutical carrier in such composition can be a watery vehicle suchas an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in Remingtons Practice ofPharmacy by E. W. Martin and E. F. Cook, a well known reference text inthis field.

In addition to the exemplary illustrations above, the following examplesfurther explain one aspect of the present invention:

Example 32 A large number of unit capsules are prepared for oraladministration by filling standard two-piece hard gelatin capsulesweighing about 30 mg. each with 5 mg. of powdered4-phenylbicyclo[2.2.2]octane-l-amine, hydrochloride, 100 mg. of lactoseand 0.2 mg. of Cab-o-sil finely divided silica.

Example 33 A large number of unit capsules are prepared for oraladministration by filling soft gelatin capsules with a solution of4-phenylbicyclo{2.2.2]octane-l-amine in mineral oil.

Example 34 Example 32 is repeated except that the dosage unit is 5 mg.of active ingredient, 5 mg. of gelatin, 3 mg. of magnesium stearate and100 mg. of mannitol, mixed and formed into a tablet by a conventionaltableting machine. Slow release pills or tablets can also be used, byapplying appropriate coatings.

20 Example 35 A parenteral composition suitable for administration byinjection is prepared by stirring 0.5% by weight of the activeingredient of Example 32 in sterile aqueous 0.9% saline.

A large variety of compositions according to this invention can thusreadily be made by substituting other compounds of this invention, andincluding specifically but not limited to compounds of this inventionthat have specifically been named hereinbefore. The compounds will beused in the amounts indicated in accordance with procedures well knownand described in the Martin and Cook text mentioned above.

The above and similar examples can be carried out in accordance with theteachings of this invention, as will be readily understood by personsskilled in the art, by substitution of components and amounts in placeof those specified. Thus, the foregoing detailed description has beengiven for clearness of understanding only and no unnecessary limitationsare to be understood therefrom.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A method of producing an anti depressant effect in warm-bloodedanimals comprising administering to said warm-blooded animal an antidepressant effective amount of a compound of the formula where R and Rare selected from the group consisting of hydrogen, alkyl of 1 through 4carbon atoms and allyl, and where R and R can be joined together to form-(Ci-I Where n is a positive integer of 4 through 6;

X and Y are selected from the group consisting of hydrogen, methyl,ethyl, cyano, chlorine, bromine, fluorine, trifluoromethyl, nitro,amino, monoalkylamino where said alkyl has 1 through 4 carbons,dialkylamino where said alkyl has 1 through 4 carbons, hydroxy, alkoxyof 1 through 4 carbons, carboxy and alkoxycarbonyl where said alkyl has1 through 2 carbons; and

the non-toxic salts of the basic compounds of said formula formed withpharmaceutically acceptable acids.

2. The method of claim 1 wherein the compound is4-phenylbicyclo[2.2.2]octane-1-amine.

3. The method of claim 1 wherein the compound is 4-phenylbicyclo[2.2.2]octane-l-amine hydrochloride.

4. The method of claim 1 wherein the compound is 4-p-fluorophenylbicyclo2.2.2] octane-l-amine.

5. The method of claim 1 wherein the compound is 4-p-fluorophenylbicyclo[2.2.2]octane-1-amine hydrochloride.

6. The method of claim 1 wherein the compound is4-p-hydroxyphenylbicyclo[2.2.2]octane-l-amine.

7. The method of claim 1 wherein the compound is4-p-hydroxyphenylbicyclo[2.2.2]octane 1 amine hydro chloride.

8. The method of claim 1 wherein the compound is 4-p-nitrophenylbicyclo[2.2.2] octane-1 -amine.

9. The method of claim 1 wherein the compound is4-p-nitrophenylbicyclo[2.2.2]octane-1 amine hydrochloride.

10. The method of claim 1 wherein the compound is4-p-tolylbicyclo[2.2.2] octane-l-amine.

11. The method of claim 1 wherein the compound is 4-p-tolylbicyclo[2.2.2] octane-l-amine hydrochloride.

12. The method of claim 1 wherein the compound isN-methyl-4phenylbicyclo [2.2.2] octanel-amine.

13. The method of claim 1 wherein the compound isN-methyl-4-phenylbicycl0[2.2.2]octane-1 amine hydrochloride.

14. The method of claim 1 wherein the compound isN-ethyl-4-phenylbicyclo[2.2.2]octane-1-amine.

15. The method of claim 1 wherein the compound is4-ethyl-4-phenylbicyclo[2.2.2]octane-1-amine hydrochloride.

16. The method of claim 1 wherein the compound is4-p-methoxy-phenylbicyclo[2.2.2] octane-1-amine.

17. The method of claim 1 wherein the compound is4-p-methoxy-phenylbicyclo [2.2.2] octane-1amine hydrochloride.

18. The method of claim 1 wherein the compound is4-p-trifluoromethylphenylbicyclo [2.2.2]octane-1-amine.

1?. The method of claim 1 wherein the compound is4-p-trifiuoromethylphenylbicyclo[2.2.2]octane 1 amine hydrochloride.

20. A composition comprising from 1 to 50% by Weight of a compound ofthe formula 22 where R and R are selected from the group consisting ofhydrogen, alkyl of 1 through 4 carbon atoms and allyl, and where R and Rcan be joined together to form (CH where n' is a positive integer of 4through 6;

X and Y are selected from the group consisting of hydrogen, methyl,ethyl, cyano, chlorine, bromine, fluorine, trifluoromethyl, nitro,amino, monoalkylamino where said alkyl has 1 through 4 carbons,dialkylamino where said alkyl has 1 through 4 carbons, hydroxy, alkoxyof 1 through 4 carbons, carboxy and alkoxycarbonyl where said alkyl has1 through 2 carbons; and

the non-toxic salts of the basic compounds of said formula formed withpharmaceutically acceptable acids; and

from 99 to by weight of a non-toxic pharmaceutical carrier for saidcompound.

21. The composition of claim 20 in tablet form containing from 1 to 500milligrams of a compound defined in claim 20 and at least onepharmaceutical carrier selected from the group consisting of gelatin,lactose and magnesium stearate.

22. The composition of claim 20 in the form of a sterile injectablesolution containing from 0.05 to 10% by Weight of a compound defined inclaim 20 dissolved in sterile saline.

References Cited FOREIGN PATENTS 1/1962 Germany. 3/1962 Germany.

ALBERT T. MEYERS, Primary Examiner.

S. I. FRIEDMAN, Assistant Examiner.

1. A METHOD OF PRODUCING AN ANTI DEPRESSANT EFFECT IN WARM-BLOODEDANIMALS COMPRISING ADMINISTERING TO SAID WARM-BLOODED ANIMAL ANANTI-DEPRESSANT EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA